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The purpose of this study was to examine, in an integrated and comprehensive fashion, three critical questions currently facing HIV-infected pregnant and postpartum women and their infants:

What is the optimal intervention for the prevention of antepartum and intrapartum transmission of HIV?

What is the optimal intervention for the prevention of postpartum transmission in breastfeeding (BF) infants?

What is the optimal intervention for the preservation of maternal health after the risk period for prevention of mother-to-child-transmission ends (either at delivery or cessation of BF)?

The overall PROMISE protocol had three separate interventional components to address each of these three questions and was conducted at locations in Africa and other parts of the world. Due to variations in the standard of care for HIV-infected pregnant and postpartum women and their infants at different sites, not all of these questions were relevant. Therefore, two separate versions of the PROMISE protocol were developed, each containing only the relevant components. The 1077BF protocol was used at sites where the standard method of infant feeding was breastfeeding, whereas the 1077FF protocol was used at sites where the standard method of infant feeding was formula feeding. The analyses were collapsed across the two protocol versions, and therefore the summaries contain the results of the 1077BF and/or the 1077FF protocols.

200 mg/300 mg x 2 tablets at onset of labor or as soon as possible thereafter; 200 mg/300 mg orally each day after delivery for 7 days or the date of the Week 1 visit (up to 14 days), whichever is later.

Drug: Nevirapine (NVP): Infant short-course

Oral suspension (dosing according to birth weight) once a day through 42 days of age or through the week 6 visit, whichever is later.

Mothers could be prescribed any licensed antiretroviral medication, as long as the treatment met the definition of HAART (three ARV drugs from two or more drug classes).

Active Comparator: Maternal Health Arm B (Discontinue triple ARVs)

Mothers discontinued triple ARV regimen.

Other: Discontinue triple ARVs

ARVs were discontinued. When protocol specified criteria were met, mothers could be prescribed any licensed antiretroviral medication, as long as the treatment met the definition of HAART (three ARV drugs from two or more drug classes).

Defined as HIV nucleic acid test (NAT) positivity of the specimen drawn at either the birth (Day 0-5) or Week 1 (Day 6-14) visit, confirmed by HIV NAT positivity of a second specimen collected at a different time point

Defined as infant HIV NAT positivity of a specimen drawn at any post-randomization visit (i.e., any visit after the Week 1 [Day 6-14] visit), confirmed by HIV NAT positivity of a second specimen drawn at a different time point. Analyses were conducted at the Mother-Infant (M-I) pair level, hence the worst outcome for multiple births was counted as a single event.

This secondary outcome required additional funding for laboratory testing. Results will be reported to ct.gov when available.

Postpartum Component: Proportion of Mother-Infant Pairs With no Death or HIV Diagnosis Through 24 Months Post-delivery [ Time Frame: Measured through 24 months post-delivery ]

Defined as infant HIV NAT positivity of a specimen drawn at any post-randomization visit, confirmed by HIV NAT positivity of a second specimen drawn at a different time point, or infant death. Analyses (Kaplan-Meier probabilities) were conducted at the Mother-Infant (M-I) pair level, hence the worst outcome for multiple births was counted as a single event.

This secondary outcome required additional funding for laboratory testing. Results will be reported to ct.gov when available.

Postpartum Component: Functional Maternal Antibody and HIV-envelope Binding Responses in Breast Milk and Plasma, Until Cessation of Breastfeeding or 18 Months Postpartum, Whichever Comes First [ Time Frame: Measured through the time of cessation of breastfeeding or 18 months postpartum, whichever comes first ]

This secondary outcome required additional funding for laboratory testing. Results will be reported to ct.gov when available.

Maternal Health Component: Incidence of Death [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]

Maternal Health Component: Incidence of AIDS-defining Illness [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]

"AIDS-defining illness" refers to the WHO Clinical Stage 4 illnesses listed in Appendix IV. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.

This secondary outcome was not included in the primary analyses. Given the results of the primary analyses the protocol team decided that this outcome was no longer scientifically important and resources should not be spent on analyzing it.

Maternal Health Component: Incidence of HIV/AIDS-related Events [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]

"HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.

Maternal Health Component: Number of Cardiovascular or Other Metabolic Events [ Time Frame: From study entry until July 7, 2015. ]

This secondary outcome was not included in the primary analyses. Given the results of the primary analyses the protocol team decided that this outcome was no longer scientifically important and resources should not be spent on analyzing it.

This secondary outcome was not included in the primary analyses. Given the results of the primary analyses the protocol team decided that this outcome was no longer scientifically important and resources should not be spent on analyzing it.

Maternal Health Component: Incidence of HIV/AIDS-related Event or Death [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]

"HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.

Maternal Health Component: Incidence of HIV/AIDS-related Event or World Health Organization (WHO) Clinical Stage 2 or 3 Events [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]

"HIV/AIDS-related event" refers to the WHO Clinical Stage 4 illnesses, pulmonary tuberculosis, and other serious bacterial infections listed in Appendix IV of the protocol. Stage 4 illnesses were reviewed and confirmed by an Endpoint review group.

Maternal Health Component: Composite Endpoint of Any Condition Outlined in Appendix IV of the Protocol or Death [ Time Frame: From study entry until July 7, 2015. ]

This secondary outcome was not included in the primary analyses. Given the results of the primary analyses the protocol team decided that this outcome was no longer scientifically important and resources should not be spent on analyzing it.

Maternal Health Component: Incidence of Tuberculosis [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]

Incidence of tuberculosis.

Maternal Health Component: Toxicity: Incidence of Grade 3 or Greater Laboratory Results or Signs and Symptoms and Selected Grade 2 Hematologic, Renal, and Hepatic Laboratory Results [ Time Frame: From study entry until July 7, 2015, an average of 94 weeks of follow-up. ]

This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. Results will be reported to ct.gov when available.

Maternal Health Component: Quality of Life [ Time Frame: From study entry until July 7, 2015. ]

This secondary outcome was not included in the primary analyses and will be defined in more detail in a separate analysis plan. Results will be reported to ct.gov when available.

Maternal Health Component: Changes in Plasma Concentrations of Inflammatory and Thrombogenic Markers [ Time Frame: From study entry until July 7, 2015. ]

This secondary outcome was not included in the primary analyses. Given the results of the primary analyses the protocol team decided that this outcome was no longer scientifically important and resources should not be spent on analyzing it.

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Ages Eligible for Study:

Child, Adult, Senior

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Antepartum Component Inclusion Criteria:

Confirmed HIV-1 infection, defined as documented positive results from two samples collected at different time points prior to study entry. More information on this criterion can be found in the protocol.

Currently pregnant and greater than or equal to 14 weeks gestation based on clinical or other obstetrical measurements

CD4 count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), on a specimen obtained within 30 days prior to study entry

Results of HBV screening (HBsAg testing) available from specimen obtained within 30 days prior to study entry

The following laboratory values from a specimen obtained within 30 days prior to study entry:

Alanine aminotransferase (ALT) less than or equal to 2.5 times the upper limit of normal (ULN)

Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women

Plans to deliver in the study-affiliated clinic or hospital

Has no plans to move outside of the study site area during the 24 months following delivery

Age of legal majority for the respective country and willing and able to provide written informed consent

Antepartum Component Exclusion Criteria:

Participation in PROMISE for a prior pregnancy

Ingestion of any antiretroviral (ARV) regimen with three or more drugs (regardless of duration) or more than 30 days of a single or dual ARV regimen during current pregnancy, according to self report or available medical records

Requires triple ARV therapy (HAART) for own health based on local standard guidelines

World Health Organization (WHO) stage 4 disease

Prior receipt of HAART for maternal treatment indications (e.g., CD4 less than 350 cells/mm^3 or clinical indications); however, could have received ARVs for the sole purpose of prevention of mother-to-child transmission (PMTCT) in previous pregnancies (prior PMTCT regimens could have included a triple ARV regimen, ZDV, 3TC-ZDV, and/or sdNVP for PMTCT, as well as use of a short dual nucleoside reverse transcriptase inhibitor [NRTI] "tail" to reduce risk of NVP resistance.)

In labor - at onset or beyond (may be eligible for the Late Presenter registration)

Current or history of tuberculosis (TB) disease (positive PPD without TB disease is not exclusionary)

Use of prohibited medications within 14 days prior to study entry (refer to the protocol for a list of prohibited medications)

Fetus detected to have serious congenital malformation (ultrasound not required to rule out this condition)

Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)

Known to meet the local standard criteria for treatment of HBV (Note: HBV DNA testing or other specialized assessments are not expected to be performed as part of this study. A woman would be excluded only if this information is documented from other sources and she meets the local standard criteria for HBV treatment based on those assessments.)

Social or other circumstances that would hinder long-term follow-up, in the opinion of the site investigator

Currently incarcerated

Late Presenter Inclusion Criteria:

Age of legal majority for the respective country

HIV-1 infection, defined as documented positive results from tests performed on one sample at any time prior to Late Presenter Registration

In labor (from onset/early labor or beyond) or within 5 days after delivery (with day of delivery considered day 0)

Has provided written informed consent

Has no plans to move outside of the study site area during the 24 months following delivery

If delivered, infant alive and healthy (In the case of a multiple birth, a mother-infant pair will be included in the Late Presenter registration only if both/all infants and the mother meet the eligibility criteria. If only one infant of a multiple birth is alive, the M-I pair may be registered if the infant and the mother otherwise meet all of the eligibility criteria.)

Late Presenter Exclusion Criteria:

Participation in PROMISE in prior pregnancy

Ingestion of any antiretroviral regimen during current pregnancy (including for solely for PMTCT), according to self report and available medical records (Note: Use of ARVs provided as standard of care for PMTCT during labor/delivery or postpartum prior to Late Presenter registration is not exclusionary.)

If known: CD4 count < 350 cells/mm3 or below the country-specific threshold for initiation of treatment, if that threshold is > 350 cells/mm3, on specimen obtained within 30 days prior to study entry (result not required prior to registration)

Requires triple ARV therapy (HAART) for own health according to local standard guidelines

WHO Stage 4 disease

Prior receipt of HAART for maternal treatment indications (e.g., CD4 < 350 cells/mm3 or clinical indications); however, could have received ARVs for the sole purpose of PMTCT in previous pregnancies. (Prior PMTCT regimens could have included a triple ARV regimen, ZDV, 3TCZDV and/or sdNVP for PMTCT, as well as use of a short dual NRTI "tail" to reduce risk of NVP resistance.)

Current or history of TB disease (positive PPD without TB disease is not exclusionary)

Fetal demise or early neonatal death (prior to enrollment/registration)

Fetus detected with serious congenital malformation (ultrasound not required to rule out this condition)

Life threatening infant illness or birth condition incompatible with life

If delivered, infant birth weight < 2.0 kg

Social or other circumstances which would hinder long-term follow-up, in the opinion of the site investigator

Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block (also known as Mobitz I or Wenckebach) is not considered exclusionary)

Postpartum Component Inclusion Criteria:

Participation in the Antepartum Component or registered as a Late Presenter

Provided written informed consent

Has no plans to move outside of the study site area during the 24 months following delivery

Maternal CD4 count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), from a specimen obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol.

The following maternal laboratory values within 30 days prior to entry:

Hemoglobin greater than or equal to 7.0 g/dL

WBC greater than or equal to 1,500 cells/mm^3

ANC greater than or equal to 750 cells/mm^3

Platelets greater than or equal to 50,000 cells/mm^3

ALT less than or equal to 2.5 times the upper limit of normal (ULN)

Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women

Infant alive, healthy, less than or equal to 14 days of age, and uninfected (negative HIV NAT result on specimen drawn prior to study entry)

The following infant lab values on specimen obtained prior to study entry (within 14 days of birth):

Hemoglobin greater than or equal to 10 g/dL

WBC greater than or equal to 1,500 cells/mm^3

ANC greater than or equal to 750 cells/mm^3

Platelets greater than or equal to 50,000 cells/mm^3

ALT less than or equal to 2.5 times the ULN

For Registered Late Presenters: Confirmed maternal HIV-1 infection, defined as documented positive results from two samples collected at different time points at any time prior to entry. More information on this criterion can be found in the protocol.

Postpartum Component Exclusion Criteria:

Positive infant HIV NAT result on specimen drawn prior to entry or no infant HIV NAT result on specimen drawn prior to entry

Life-threatening infant illness or birth condition incompatible with life

Infant birth weight less than 2.0 kg

Social or other circumstances that would hinder long-term follow-up, as judged by the site investigator

Current or history of TB disease (positive PPD without TB disease is not exclusionary)

Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)

Requires triple ARV therapy (HAART) for own health

Maternal Health Component Inclusion Criteria:

Randomly assigned to triple ARV prophylaxis as part of the Postpartum Component and has continued triple ARV prophylaxis until the current randomization without treatment interruption (defined as more than 14 consecutive days of missed dosing) within the previous 30 days; OR randomly assigned to triple ARV prophylaxis in the Antepartum Component but ineligible for the Postpartum Component and has continued triple ARV prophylaxis until the current randomization without treatment interruption (defined as more than 7 consecutive days of missed dosing) within the previous 30 days

Within two weeks after complete breastfeeding cessation is achieved (defined as completely stopping all exposure to breast milk for greater than or equal to 28 days); i.e., within 29 to 42 days of last breast milk exposure, or reached 18 months postpartum (whichever comes first). Women who reach 18 months postpartum while still breastfeeding will be eligible for entry within 2 weeks before and 4 weeks after the Week 74 visit (Week 72-78); OR if the woman was randomized to triple ARV prophylaxis in the Postpartum Component and her infant is infected and still breastfeeding, she will be eligible for the Maternal Health Component within 42 days of specimen collection for the confirmatory infant HIV NAT; OR if the woman was randomized to triple ARV prophylaxis in the Antepartum Component but mother-infant pair was ineligible for the Postpartum Component she will be eligible for the Maternal Health Component beginning at the Week 1 visit (6-14 days postpartum) through 28 days after delivery; these women should be randomized as soon as possible, ideally within 6-14 days after delivery; OR if the woman was randomized to triple ARV prophylaxis in the Postpartum Component and breastfeeding risk for MTCT ceases for other reasons (e.g., infant death or permanent removal from home through legal services or adoption) within 28 days of event. More information on this criterion can be found in the protocol.

Provided written informed consent

CD4 cell count greater than or equal to 350 cells/mm^3, or greater than or equal to the country-specific threshold for initiation of treatment (if that threshold is greater than 350 cells/mm^3), on a specimen obtained within 30 days prior to study entry

The following laboratory values on a specimen obtained within 30 days prior to study entry:

ANC greater than or equal to 750 cells/mm^3

Hemoglobin greater than or equal to 7.0 gm/dL

Platelet count greater than or equal to 50,000 cells/mm^3

ALT (SGPT) less than or equal to 2.5 times the ULN

Estimated creatinine clearance of greater than or equal to 60 mL/min using the Cockroft-Gault equation for women

Intend to remain in current geographical area of residence for the duration of study

Current or history of TB disease (positive PPD without TB disease is not exclusionary)

Use of prohibited medications within 14 days prior to study entry

Social or other circumstances that would hinder long term follow-up as judged by the site investigator

Current documented conduction heart defect (specialized assessments to rule out this condition are not required; a heart murmur alone and/or type 1 second-degree atrioventricular block [also known as Mobitz I or Wenckebach] is not considered exclusionary)

U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0. [Updated August 2009]. Available from: http://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf

WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV-related Disease in Adults and Children, World Health Organization, 2007. Available: http://apps.who.int/iris/handle/10665/43699